Process for Producing Cyclopentanone-2, 3, 5-Tricarboxylic Acid Triester

ABSTRACT

The present invention provide a process that allows the industrially advantageous production of a cyclopentanone-2,3,5-tricarboxylic acid triester. Namely, the present invention provides a process for producing a cyclopentanone-2,3,5-tricarboxylic acid triester represented by the general formula (IV), characterized by comprising: (1) allowing an itaconic acid diester represented by the general formula (I) to react with a metal salt of malonic acid diester represented by the general formula (II) to obtain a reaction mixture containing an adduct represented by the general formula (III); and then (2) allowing said reaction mixture to react with an alcohol or a metal alkoxide, or a mixture thereof: 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  each independently represents an alkyl group which may have a substituent, and M represents an alkali metal.

TECHNICAL FIELD

The present invention relates to a process for producing acyclopentanone-2,3,5-tricarboxylic acid triester. Thecyclopentanone-2,3,5-tricarboxylic acid triester obtainable by thepresent invention is suitable for use as an intermediate in thesynthesis of 3-oxocyclopentane-1-carboxylic acid or ester thereof, whichis an intermediate of xanthine derivatives that are useful as adenosineantagonists (see JP-A-7-509492).

BACKGROUND ART

Conventionally, a method for producingcyclopentanone-2,3,5-tricarboxylic acid triester, which is comprised ofallowing dimethyl itaconate to react with sodium salt of dimethylmalonate that is prepared from sodium hydride and dimethyl malonate,isolating a product (tetramethyl 1,1,3,4-butanetetracarboxylate) fromresulting reaction mixture by purification with distillation afterneutralizing with an acid, and then cyclizing the product in thepresence of not less than one equivalent of sodium methoxide, andisolating a target compound from resultant reaction mixture afterneutralizing with an acid, has been known (see U.S. Pat. No. 4,272,437,columns 361-362).

The above-mentioned conventional process requires twice neutralizationtreatment including that after the cyclization step, furtherpurification with distillation, and the like, because of isolating areaction product of dimethyl itaconate and sodium salt of dimethylmalonate once. These make steps very vexatious and complicated.Moreover, 1.07 molar equivalents of sodium methoxide is used as a basein the cyclization step, thereby the waste discharged from theneutralization treatment necessarily increases leading to a heavy loadto the environment. Furthermore, yield of acyclopentanone-2,3,5-tricarboxylic acid trimethylester is as low as 50%based on dimethylitaconate. Consequently, these problems make theconventional process unsuited to industrial applications, and theprocess has a room to be improved.

Accordingly, an object of the present invention is to provide a processthat allows the industrially advantageous production of acyclopentanone-2,3,5-tricarboxylic acid triester with a simple andconvenient after-treatment and less waste.

The present inventors have diligently researched in order to solve theproblems of the conventional process, and discovered as a result that byallowing an itaconic acid diester to react with a metal salt of malonicacid diester, and allowing obtained reaction mixture to react with analcohol or a metal alkoxide, or a mixture-thereof, conversion to thedesired cyclopentanone-2,3,5-tricarboxylic acid triester is enabledwithout isolating an adduct of an itaconic acid diester and a metal saltof malonic acid diester, or the adduct with neutralized form, which areintermediates, and accomplished the present invention.

DISCLOSURE OF THE INVENTION

Namely, the present invention provides a process for producing acyclopentanone-2,3,5-tricarboxylic acid triester represented by thegeneral formula (IV):

wherein R⁵, R⁶, and R⁷ each independently represents an alkyl groupwhich may have a substituent (hereinafter referred to ascyclopentanone-2,3,5-tricarboxylic acid triester (IV)); characterized bycomprising:

-   (1) allowing an itaconic acid diester represented by the general    formula (I):

wherein R¹ and R² each independently represents an alkyl group which mayhave a substituent (hereinafter referred to as itaconic acid diester(I)); to react with a metal salt of malonic acid diester represented bythe general formula (II)

wherein R³ and R⁴ each independently represents an alkyl group which mayhave a substituent, and M represents an alkali metal (hereinafterreferred to as metal salt of malonic acid diester (II)]; to obtain areaction mixture containing an adduct represented by the general formula(III):

wherein R¹, R², R³, R⁴, and M are as defined above (hereinafter referredto as adduct (III)); (hereinafter this step may be referred to as step(1)) and then

-   (2) allowing said reaction mixture to react with an alcohol or a    metal alkoxide, or a mixture thereof (hereinafter, this step may be    referred to as step (2)).

Moreover, in a preferable embodiment, a mixture of an alcohol and ametal alkoxide is used in the above step (2), and furthermore, an amountof the metal alkoxide used is not more than one molar equivalent withrespect to itaconic acid diester (I).

According to the present invention, a process that allows theindustrially advantageous production of acyclopentanone-2,3,5-tricarboxylic acid triester can be produced in highyield, with a easy after-treatment and less waste is provided.

BEST MODE FOR CARRYING OUT THE INVENTION

The alkyl group that R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ each independentlyrepresents in the above general formulae is preferably a linear,branched or cyclic alkyl group having 1 to 12 carbon atoms, such asmethyl group, ethyl group, propyl group, isopropyl group, butyl group,hexyl group, octyl group, dodecyl group, cyclopentyl group, cyclohexylgroup, and the like.

The alkali metal that M represents is such as lithium, sodium,potassium, and the like.

First, step (1), namely, a step in which itaconic acid diester (I) andmetal salt of malonic acid diester (II) are reacted, will be described.

The metal salt of malonic acid diester (II) can be simply andconveniently prepared by allowing a base containing an alkali metal toreact with a corresponding malonic acid diester. Examples of the baseinclude alkali metal hydrides such as lithium hydride and sodiumhydride; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, and potassium hydroxide; alkali metal alkoxides such assodium methoxide, sodium ethoxide, potassium methoxide, and potassiumethoxide; and organic alkali metal compounds such as methyllithium andn-butyllithium; and the like. Of these, when an alkali metal hydroxideor an alkali metal alkoxide is used as the base, it is preferably toremove generated water or an alcohol out of the reaction system beforecarrying out the reaction of itaconic acid diester (I) with metal saltof malonic acid diester (II), because said water or an alcohol may causeside reaction in said reaction.

An amount of itaconic acid diester (I) used maybe selected asappropriate in consideration with reaction efficiency and conversion ofitaconic acid diester (I), but is generally in a range of 0.5 to 10equivalents, preferably in a range of 0.5 to 2 equivalents with respectto metal salt of malonic acid diester (II).

The reaction is preferably carried out in the presence of a solvent.There are no particular restrictions on the solvent as long as it doesnot adversely affect the reaction, and examples of such solvent includealiphatic hydrocarbons such as hexane, heptane and octane; aromatichydrocarbons such as benzene, toluene, xylene, ethylbenzene andmesitylene; and ethers such as tetrahydrofuran, diethyl ether,diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane,1,4-dioxane and diethyleneglycol dimethyl ether; and the like. Thesesolvents may be used singly or in a mixture of two or more. Of these,from the viewpoint of ease of treatment in carrying out theneutralization treatment after completion of all reactions, it ispreferred to use a solvent which is immiscible in water, and it is morepreferred to use toluene or diisopropyl ether.

Reaction temperature is generally selected from a range of −20 to 100°C.

The step (1) can be carried out, for example, by adding itaconic aciddiester (I) or a mixture of itaconic acid diester (I) and a solvent to amixture containing metal salt of malonic acid diester (II) and asolvent, or by adding metal salt of malonic acid diester (II) to amixture of itaconic acid diester (I) and a solvent. Time required forthe addition is not particularly restricted, but generally in a range of0.5 to 10 hours from the viewpoint of controlling reaction temperature,because the step (1) is an exothermal reaction. Reaction time is notparticularly restricted, but generally in a range of 0.5 to 20 hours.

Although, the reaction mixture obtained in the step (1) contains adduct(III), the present invention is characterized by subjecting the reactionmixture to the step (2) described below without isolating adduct (III)with neutralized form from adduct (III), to obtain acyclopentanone-2,3,5-tricarboxylic acid triester.

Secondly, step (2), namely, a step in which the above-mentioned reactionmixture obtained in the step (1) is reacted with an alcohol or a metalalkoxide, or a mixture thereof, will be described.

The step (2) can be carried out by adding an alcohol to the reactionmixture obtained in the above step (1). Examples of the alcohol includemethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,2-methyl-2-propanol, 1-pentanol, 1-hexanol, 1-octanol and the like.These alcohols may be used singly or in a mixture of two or more. Anamount of alcohol used is not particularly restricted, and when thereare many amount of the alcohol used, the reaction rate can be enhancedgenerally. However, the amount may be selected appropriately from theviewpoints of solubility of the reaction mixture, reaction temperature,reaction time, ease of isolation treatment for the reaction product orthe like, and generally in a range of 0.1 to 5 times by mole withrespect to itaconic acid diester (I).

In the present invention, by further using a metal alkoxide in additionto an alcohol, reaction rate of the step (2) can be enhanced. Moreover,even by using only a metal alkoxide, the step (2) can be carried out.Examples of such metal alkoxide include alkali metal alkoxides such aslithium methoxide, lithium ethoxide, lithium tert-butoxide, sodiummethoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide,potassium ethoxide and potassium tert-butoxide; alkaline-earth metalalkoxides such as magnesium dimethoxide, magnesium diethoxide, calciumdimethoxide and calcium diethoxide; and the like. These metal alkoxidesmay be used singly or in a mixture of two or more. An amount of themetal alkoxide used may be selected appropriately from the viewpoints ofreaction temperature, reaction time, and reaction solvent or the like,but is preferably in a range of 0.01 to 1 molar equivalent, and morepreferably in a range of 0.05 to 0.2 molar equivalent with respect toitaconic acid diester (I), from the viewpoint of reducing amount of awaste in the neutralization treatment.

When an alcohol and a metal alkoxide are used as a mixture, mixing ratiothereof is not particularly restricted, and an amount of the metalalkoxide used in the alcohol is preferably not more than one molarequivalent with respect to itaconic acid diester (I). In addition, whenan alcohol and a metal alkoxide are used as a mixture, a kind of thealcohol is allowed to be different from alcohol source forming the metalalkoxide.

The reaction is preferably carried out in the presence of a solvent. Asthe solvent, preferably the solvent used in the step. (I) continues tobe used as it is, but another solvent may be added freshly. There are noparticular restrictions on the solvent added freshly as long as it doesnot adversely affect the reaction, and examples of the solvent includealiphatic hydrocarbons such as hexane, heptane and octane; aromatichydrocarbons such as benzene, toluene, xylene, ethylbenzene andmesitylene; ethers such as tetrahydrofuran, diethyl ether, diisopropylether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane anddiethyleneglycol dimethyl ether; and the like.

Reaction temperature is generally selected from a range of 0° C. to atemperature at which reaction mixture is refluxed. Reaction time is notparticularly restricted, but generally in a range of 1 to 30 hours.

The step (2) may be carried out by adding an alcohol or a metalalkoxide, or a mixture thereof to the reaction mixture obtained in theabove step (1) at the predetermined temperature.

Cyclopentanone-2,3,5-tricarboxylic acid triester (IV) obtained in thismanner can be isolated and purified by means ordinarily employed in theisolation and purification of an organic compound. For example, anacidic aqueous solution is added to the reaction mixture to neutralize.After the aqueous layer is separated, the organic layer is concentrated,and the resultant crude product is purified by column chromatography,recrystallization, distillation or the like.

EXAMPLES

The present invention will now be described in detail with reference toExamples and are not intended to limit the scope of the presentinvention any way.

Example 1

Toluene (600 ml) and 60% sodium hydride (30 g, 748 mmol) were placed ina reaction vessel having a capacity of 2 L. Dimethyl malonate (96 g, 726mmol) was added dropwise to the solution over one hour with the internaltemperature kept below 30° C. After completion of the dropping, asolution obtained by dissolving dimethyl itaconate (113 g, 712 mmol) intoluene (400 ml) was added dropwise over one hour with the internaltemperature kept below 30° C. Subsequently, after the mixture wasreacted for 3 hours with the internal temperature kept at 25° C., 28%sodium methoxide solution in methanol (14.0 g, 71 mmol) was then addedthereto, and the mixture was heated at the internal temperature of 70°C. for 5 hours. The resultant reaction mixture was cooled to atemperature not higher than 20° C., and20% sulfuric acid aqueoussolution (300 ml) was added dropwise over 10 minutes with the internaltemperature kept below 30° C. The reaction mixture was allowed to standfor separation. After confirming that a pH of an aqueous layer was nothigher than 3, an organic layer was separated. The organic layer waswashed with saturated sodium hydrogen carbonate aqueous solution(100ml), concentrated under reduced pressure, and the residue waspurified using silica gel column chromatography to obtain 156.1 g ofcyclopentanone-2,3,5-tricarboxylic acid trimethylester (yield: 85%).

Example 2

The similar reactions and after-treatments were carried out as inExample 1, except that a powdery sodium methoxide (3.92 g, 71 mmol) wasused instead of 28% sodium methoxide solution in methanol (14.0 g, 71mmol) and the reaction time after completion of adding the sodiummethoxide was changed to 20 hours, to obtain 132.2 g ofcyclopentanone-2,3,5-tricarboxylic acid trimethylester (yield: 72%).

Example 3

The similar reactions and after-treatments were carried out as inExample 1, except that an amount of 60% sodiumhydride used is changedfrom 30 g to 28 g (700 mmol), methanol (100 ml) was used instead of 28%sodium methoxide solution in methanol (14.0 g, 71 mmol), and thereaction time was changed from 5 hours to 10 hours, to obtain 148.8 g ofcyclopentanone-2,3,5-tricarboxylic acid trimethylester (yield: 81%).

INDUSTRIAL APPLICABILITY

Cyclopentanone-2,3,5-tricarboxylic acid triester obtainable by thepresent invention is suitable for use as an intermediate in thesynthesis of 3-oxocyclopentane-1-carboxylic acid or ester thereof, whichis an intermediate of xanthine derivatives that are useful as adenosineantagonists (see JP-A-7-509492).

1. A process for producing a cyclopentanone-2,3,5-tricarboxylic acidtriester represented by the general formula (IV):

wherein R⁵, R⁶, and R⁷ each independently represents an alkyl groupwhich may have a substituent; the process comprising: (1) allowing anitaconic acid diester represented by the general formula (I):

wherein R¹ and R² each independently represents an alkyl group which mayhave a substituent; to react with a metal salt of malonic acid diesterrepresented by the general formula (II):

wherein R³ and R⁴ each independently represents an alkyl group which mayhave a substituent, and M represents an alkali metal; to obtain areaction mixture containing an adduct represented by the general formula(III):

wherein R¹, R², R³, R⁴, and M are as defined above; and then (2)allowing said reaction mixture without isolating the adduct (III) fromsaid reaction mixture to react with an alcohol and a metal alkoxidemixture to form the cyclopentanone-2,3,5-tricarboxylic acid triesterrepresented by the general formula (IV).
 2. The process for producing acyclopentanone-2,3,5-tricarboxylic acid triester according to claim 1,wherein an amount of the metal alkoxide used is not more than one molarequivalent with respect to an itaconic acid diester represented by thegeneral formula (I):

wherein R¹ and R² each independently represents an alkyl group which mayhave a substituent.
 3. The process for producing acyclopentanone-2,3,5-tricarboxylic acid triester according to claim 1,wherein an amount of the metal alkoxide is in a range of 0.01 to 1 molarequivalent with respect to the itaconic acid diester.